Substituted biaryl derivatives and methods of use thereof

ABSTRACT

The present invention relates to Substituted Biaryl Derivatives, compositions comprising a Substituted Biaryl Derivative, and methods of using the Substituted Biaryl Derivatives for treating or preventing obesity, diabetes, a metabolic disorder, a cardiovascular disease or a disorder related to the activity of GPR119 in a patient.

FIELD OF THE INVENTION

The present invention relates to Substituted Biaryl Derivatives,compositions comprising a Substituted Biaryl Derivative, and methods ofusing the Substituted Biaryl Derivatives for treating or preventingobesity, diabetes, a diabetic complication, a metabolic disorder, acardiovascular disease or a disorder related to the activity of a Gprotein-coupled receptor (GPCR) in a patient.

BACKGROUND OF THE INVENTION

Although a number of receptor classes exist in humans, by far the mostabundant and therapeutically relevant is represented by the GPCR class.It is estimated that there are some 100,000 genes within the humangenome, and of these, approximately 2% or 2,000 genes, are estimated tocode for GPCRs. Receptors, including GPCRs, for which the endogenousligand has been identified are referred to as “known” receptors, whilereceptors for which the endogenous ligand has not been identified arereferred to as “orphan” receptors. GPCRs represent an important area forthe development of pharmaceutical products, as evidenced by the factthat pharmaceutical products have been developed from approximately 20of the 100 known GPCRs. This distinction is not merely semantic,particularly in the case of GPCRs.

GPCRs share a common structural motif. All these receptors have sevensequences of between 22 to 24 hydrophobic amino acids that form sevenalpha helices, each of which spans the membrane (each span is identifiedby number, i.e., transmembrane-1 (TM-1), transmembrane-2 (TM-2), etc.).The transmembrane helices are joined by strands of amino acids betweentransmembrane-2 and transmembrane-3, transmembrane-4 andtransmembrane-5, and transmembrane-6 and transmembrane-7 on theexterior, or “extracellular” side, of the cell membrane (these arereferred to as “extracellular” regions 1, 2 and 3 (EC-1, EC-2 and EC-3),respectively). The transmembrane helices are also joined by strands ofamino acids between transmembrane-1 and transmembrane-2, transmembrane-3and transmembrane-4, and transmembrane-5 and transmembrane-6 on theinterior, or “intracellular” side, of the cell membrane (these arereferred to as “intracellular” regions 1, 2 and 3 (IC-1, IC-2 and IC-3),respectively). The “carboxy” (“C”) terminus of the receptor lies in theintracellular space within the cell, and the “amino” (“N”) terminus ofthe receptor lies in the extracellular space outside of the cell.

Generally, when an endogenous ligand binds with the receptor (oftenreferred to as “activation” of the receptor), there is a change in theconformation of the intracellular region that allows for couplingbetween the intracellular region and an intracellular “G-protein.” Ithas been reported that GPCRs are “promiscuous” with respect to Gproteins, i.e., that a GPCR can interact with more than one G protein.See, Kenakin, T., Life Sciences 43, 1095 (1988). Although other Gproteins exist, currently, Gq, Gs, Gi, and Go are G proteins that havebeen identified. Endogenous ligand-activated GPCR coupling with theG-protein begins a signaling cascade process (referred to as “signaltransduction”). Under normal conditions, signal transduction ultimatelyresults in cellular activation or cellular inhibition. It is thoughtthat the IC-3 loop as well as the carboxy terminus of the receptorinteract with the G protein.

Under physiological conditions, GPCRs exist in the cell membrane inequilibrium between two different conformations: an “inactive” state andan “active” state. A receptor in an inactive state is unable to link tothe intracellular signaling transduction pathway to produce a biologicalresponse. Changing the receptor conformation to the active state allowslinkage to the transduction pathway (via the G-protein) and produces abiological response. A receptor can be stabilized in an active state byan endogenous ligand or a compound such as a drug.

Modulation of G-protein coupled receptors has been well-studied forcontrolling various metabolic disorders. Small molecule modulators ofthe receptor GPR119, a G-protein coupled-receptor described in, forexample, Gen Bank (see, e.g., accession numbers XM.sub.—066873 andAY288416), have been shown to be useful for treating or preventingcertain metabolic disorders. GPR119 is a G protein-coupled receptor thatis selectively expressed on pancreatic beta cells. GPR119 activationleads to elevation of a level of intracellular cAMP, consistent withGPR119 being coupled to Gs. Agonists to GPR119 stimulateglucose-dependent insulin secretion in vitro and lower an elevated bloodglucose level in vivo. See, e.g., International Publication Nos. WO04/065380, WO 041076413, and EP 1338651, the disclosure of each of whichis herein incorporated by reference in its entirety.

U.S. patent application Ser. No. 10/890,549 disclosespyrazolo[3,4-d]pyrimidine ethers and related compounds as modulators ofthe GPR119 receptor that are useful for the treatment of variousmetabolic-related disorders such as type I diabetes, type II diabetes,inadequate glucose tolerance, insulin resistance, hyperglycemia,hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemiaor syndrome X. The compounds are also reported as being useful forcontrolling weight gain, controlling food intake, and inducing satietyin mammals. The promising nature of these GPCR modulators indicates aneed in the art for additional small molecule GPCR modulators withimproved efficacy and safety profiles. This invention addresses thatneed.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides Compounds of Formula (I):

and pharmaceutically acceptable salts, solvates, esters, prodrugs andstereoisomers thereof, wherein:

A is selected from:

B is selected from:

Q is —O—, —S—, —NH—, —N(R¹⁵)—, —S(O)—, —S(O)(R¹⁵)— or —S(O)₂—;

W is a bond, alkylene, —C(O)—, —C(O)—O—, —C(O)—S—, —S(O)—, —S(O)₂—,—S(O)₂—N(R¹⁰)— or —C(O)—N(R¹⁰)—;

X is halo, —CF₃, —CN, —OH, —SR¹⁵, —S(O)₂R¹⁵, —S(O)₂NHR¹⁵,—S(O)₂N(R¹⁵)(C₁₋₅alkyl), —C(O)R¹⁵, —C(O)OR¹⁵, —S(O)₂N(R¹⁶)(R¹⁷),—C(O)NHR¹⁷, —C(O)N(R¹⁶)(R¹⁷), —NHS(O)₂R¹⁵, —C(O)NHR¹⁵, aryl or -5- or6-membered heteroaryl, wherein an aryl or -5-- or 6-membered heteroarylcan be optionally substituted by one or more substituents, which can bethe same or different, and are selected from halo, —CF₃, alkyl,C₃₋C₇cycloalkyl, —CN, —OR¹⁵, —N(R¹⁶)(R¹⁷) and —NO₂;

Y is a bond or C₁-C₃alkylene;

Z is a bond, —C(O)—, —C(═NOR¹²)—, —C(_(R) ¹⁴)═, —C(R¹⁴)—, —C(R¹)₂—, —O—,—N(R¹⁰)— or —S(O)_(n)—;

each occurrence of R¹ is independently H, alkyl, C₃-C₇cycloalkyl, haloor —OR⁷; wherein an alkyl group can be unsubstituted or optionallysubstituted with one or more of the following groups: —O-alkyl, —OH or—N(R⁴)₂; and wherein any two geminal R¹ groups, together with the commoncarbon atom to which they are attached, can join to form a spirocyclic3- to 6-membered cycloalkyl group, a spirocyclic 3- to 6-memberedheterocycloalkyl group or a spirocyclic 3- to 6-memberedheterocycloalkenyl group; and wherein any two R¹ groups present onseparate ring carbon atoms can join to form a C₃-C₇cycloalkyl orheterocycloalkyl bridge; and wherein any particular R¹ group is —OH,then any other R¹ group attached to the same carbon atom must be otherthan halo or —OR⁷;

each occurrence of R² is independently H or alkyl;

R³ is alkyl, -alkenyl, -alkynyl, -(alkylene)_(t)-C(O)R⁴, -haloalkyl,-alkylene-O-alkyl, -alkylene-O-(alkylene)_(t)-aryl,-alkylene-S(O)_(n)-aryl, -alkylene-N(R⁴)C(O)O-alkyl,—CH(C₃-C₇cycloalkyl)₂, —CH(heterocycloalkyl)₂, -(alkylene)_(t)-aryl,-(alkylene)_(t)-C₃-C₇cycloalkyl, -(alkylene)_(t)-cycloalkenyl,-(alkylene)_(t)-heterocycloalkyl, -(alkylene)_(t)-heterocycloalkenyl or-(alkylene)_(t)-heteroaryl, wherein an aryl, C₃-C₇cycloalkyl,cycloalkenyl, heterocycloalkyl, heterocycloalkenyl or heteroaryl groupcan be unsubstituted or optionally substituted with R⁹;

each occurrence of R⁴ is H, alkyl, C₃-C₇cycloalkyl or alkenyl, whereinan alkyl group can be optionally substituted with halo, —OH or —O-alkyl;

each occurrence of R⁶ is a ring carbon atom substituent and isindependently selected from halo, —CF₃, —OH, alkyl, C₃-C₇cycloalkyl and—O-alkyl;

each occurrence of R^(ea) is a ring carbon atom substituent and isindependently selected from halo, —CF₃, —OH, alkyl, C₃-C₇cycloalkyl and—O-alkyl;

R⁷ is H or alkyl;

R⁸ is H, alkyl, -alkylene-(C₃-C₇cycloalkyl) or C₃-C₇cycloalkyl, or R⁸,R¹¹ and the common carbon atom to which each are attached, combine toform a C₃-C₇cycloalkyl group;

R⁹ represents from 1 to 4 optional substituents, which can be the sameor different, and which are selected from alkyl, alkenyl, alkynyl, halo,haloalkyl, —CN, —NO₂, —O-(alkylene)_(t)R¹³, —S-(alkylene)_(t)-R¹³,—N(R¹³)-(alkylene)_(t)-R¹³, -(alkylene)_(t)-R¹³,—C(O)-(alkylene)_(t)-R¹³, —C(O)O-(alkylene)_(t)-R¹³,—N(R⁷)C(O)-(alkylene)_(t)-R¹³, —C(O)N(R⁷)-(alkylene)_(t)-R¹³,—OC(O)-(alkylene)_(t)-R¹³, —N(R⁷)C(O)N(R⁷)-(alkylene)t-R¹³,—N(R⁷)C(O)O-(alkylene)_(t)R¹³, —S(O)-(alkylene)_(t)-R¹³ or—S(O)₂(alkylene)_(t)-R¹³;

R¹⁰ is H, alkyl, aryl, or —C(O)OR⁴, wherein an alkyl group isunsubstituted or optionally substituted with —OH or —O-alkyl;

R¹¹ is H, alkyl, -alkylene-(C₃-C₇cycloalkyl) or C₃-C₇cycloalkyl;

R¹² is H, alkyl or aryl;

each occurrence of R¹³ is independently H, haloalkyl, aryl,C₃-C₇cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl orheteroaryl;

each occurrence of R¹⁴ is independently H, alkyl or aryl, or both R¹⁴groups, and the carbons atom to which they are attached, combine to forma 5 to 7-membered cycloalkenyl group or a 5 to 7-memberedheterocycloalkenyl group;

R¹⁵ is alkyl, C₃-C₇cycloalkyl, phenyl, -(alkylene)-phenyl, heteroaryl,-3- to 7-membered heterocycloalkyl or -alkylene-(3- to 7-memberedheterocycloalkyl), wherein a C₃-C₇cycloalkyl, heteroaryl, phenyl orheterocycloalkyl group can be optionally substituted by one or moregroups, which can be the same or different, and are selected from halo,—OH, —O-alkyl, a heteroaryl ring of 5-6 members, —N(R¹⁶)(R¹⁷) and—C(O)N(R¹⁶)(R¹⁷);

R¹⁶ and R¹⁷ are each independently selected from the group consisting ofH, alkyl, C₃-C₇cycloalkyl, —C(O)O-alkyl and C₃-C₇cycloalkyl, or R¹⁶ andR¹⁷, when attached to a common nitrogen atom, combine with the commonnitrogen atom to which they are attached and form a C₃-C₇cycloalkyl or a-4- to 7-membered heterocycloalkyl, each of which can optionally haveone of its ring carbon atoms replaced with a —C(O)-group;

each occurrence of m is independently an integer ranging from 0 to 4,such that the total number of R⁶ and R^(6a) groups present on any A or Bgroup, respectively, cannot exceed the number of ring carbon atomscontained by the rings to which R⁶ and R^(6a) are attached;

each occurrence of n is independently 0, 1 or 2;

p is 0, 1 or 2;

q is 0, 1 or 2;

r is 0, 1 or 2;

s is 0, 1 or 2;

each occurrence of t is independently 0 or 1; and

u is 0, 1 or 2.

The Compounds of Formula (I) and pharmaceutically acceptable salts,solvates, esters or prodrugs thereof (referred to collectively herein asthe “Substituted Biaryl Derivatives”) can be useful for treating orpreventing obesity, diabetes, a diabetic complication, metabolicsyndrome, a cardiovascular disease or a disorder related to the activityof a GPCR (each being a “Condition”) in a patient.

Also provided by the invention are methods for treating or preventing aCondition in a patient, comprising administering to the patient aneffective amount of one or more Substituted Biaryl Derivatives.

The present invention further provides compositions comprising aneffective amount of one or more Substituted Biaryl Derivatives or apharmaceutically acceptable salt, solvate, ester, prodrug orstereoisomer thereof, and a pharmaceutically acceptable carrier. Thecompositions can be useful for treating or preventing a Condition in apatient.

The details of the invention are set forth in the accompanying detaileddescription below.

Although any methods and materials similar to those described herein canbe used in the practice or testing of the present invention,illustrative methods and materials are now described. Other features,objects, and advantages of the invention will be apparent from thedescription and the claims. All patents and publications cited in thisspecification are incorporated herein by reference.

DETAILED DESCRIPTION OF THE INVENTION

In an embodiment, the present invention provides Substituted BiarylDerivatives of Formula (I), compositions comprising one or moreSubstituted Biaryl Derivatives, and methods of using the SubstitutedBiaryl Derivatives for treating or preventing a Condition in a patient.

Definitions and Abbreviations

As used above, and throughout this disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

A “patient” is a human or non-human mammal. In one embodiment, a patientis a human. In another embodiment, a patient is a non-human mammal,including, but not limited to, a monkey, dog, baboon, rhesus, mouse,rat, horse, cat or rabbit. In another embodiment, a patient is acompanion animal, including but not limited to a dog, cat, rabbit, horseor ferret. In one embodiment, a patient is a dog. In another embodiment,a patient is a cat.

The term “obesity” as used herein, refers to a patient being overweightand having a body mass index (BMI) of 25 or greater. In one embodiment,an obese patient has a BMI of 25 or greater. In another embodiment, anobese patient has a BMI from 25 to 30. In another embodiment, an obesepatient has a BMI greater than 30. In still another embodiment, an obesepatient has a BMI greater than 40.

The term “obesity-related disorder” as used herein refers to: (i)disorders which result from a patient having a BMI of 25 or greater; and(ii) eating disorders and other disorders associated with excessive foodintake. Non-limiting examples of an obesity-related disorder includeedema, shortness of breath, sleep apnea, skin disorders and high bloodpressure.

The term “metabolic syndrome” as used herein, refers to a set of riskfactors that make a patient more succeptible to cardiovascular diseaseand/or type 2 diabetes. A patient is said to have metabolic syndrome ifthe patient simultaneously has three or more of the following five riskfactors:

-   -   1) central/abdominal obesity as measured by a waist        circumference of greater than 40 inches in a male and greater        than 35 inches in a female;    -   2) a fasting triglyceride level of greater than or equal to 150        mg/dL;    -   3) an HDL cholesterol level in a male of less than 40 mg/dL or        in a female of less than 50 mg/dL;    -   4) blood pressure greater than or equal to 130/85 mm Hg; and    -   5) a fasting glucose level of greater than or equal to 110        mg/dL.

The term “effective amount” as used herein, refers to an amount of aSubstituted Biaryl Derivative and/or an additional therapeutic agent, ora composition thereof, that is effective in producing the desiredtherapeutic, ameliorative, inhibitory or preventative effect whenadministered to a patient suffering from a Condition. In the combinationtherapies of the present invention, an effective amount can refer toeach individual agent or to the combination as a whole, wherein theamounts of all agents administered are together effective, but whereinthe component agent of the combination may not be present individuallyin an effective amount.

The term “alkyl,” as used herein, refers to an aliphatic hydrocarbongroup which may be straight or branched and which contains from about 1to about 20 carbon atoms. In one embodiment, an alkyl group containsfrom about 1 to about 12 carbon atoms. In another embodiment, an alkylgroup contains from about 1 to about 6 carbon atoms. Non-limitingexamples of alkyl groups include methyl, ethyl, n-propyl, isopropyl,n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl,isopentyl, n-hexyl, isohexyl and neohexyl. An alkyl group may beunsubstituted or substituted by one or more substituents which may bethe same or different, each substituent being independently selectedfrom the group consisting of halo, alkenyl, alkynyl, aryl, cycloalkyl,cyano, hydroxy, —O-alkyl, —O-aryl, -alkylene-O-alkyl, alkylthio, —NH₂,—NH(alkyl), —N(alkyl)₂, —NH(cycloalkyl), —O—C(O)-alkyl, —O—C(O)-aryl,—O—C(O)-cycloalkyl, —C(O)OH and —C(O)O-alkyl. In one embodiment, analkyl group is unsubstituted. In another embodiment, an alkyl group islinear. In another embodiment, an alkyl group is branched.

The term “alkenyl,” as used herein, refers to an aliphatic hydrocarbongroup containing at least one carbon-carbon double bond and which may bestraight or branched and contains from about 2 to about 15 carbon atoms.In one embodiment, an alkenyl group contains from about 2 to about 12carbon atoms. In another embodiment, an alkenyl group contains fromabout 2 to about 6 carbon atoms. Non-limiting examples of alkenyl groupsinclude ethenyl, propenyl, n-butenyl, 3-methylbut -2-enyl, n-pentenyl,octenyl and decenyl. An alkenyl group may be unsubstituted orsubstituted by one or more substituents which may be the same ordifferent, each substituent being independently selected from the groupconsisting of halo, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy,—O-alkyl, —O-aryl, -alkylene-O-alkyl, alkylthio, —NH₂, —NH(alkyl),—N(alkyl)₂, —NH(cycloalkyl), —O—C(O)-alkyl, —O—C(O)-aryl,—O—C(O)-cycloalkyl, —C(O)OH and —C(O)O-alkyl. In one embodiment, analkenyl group is unsubstituted.

The term “alkynyl,” as used herein, refers to an aliphatic hydrocarbongroup containing at least one carbon-carbon triple bond and which may bestraight or branched and contains from about 2 to about 15 carbon atoms.In one embodiment, an alkynyl group contains from about 2 to about 12carbon atoms. In another embodiment, an alkynyl group contains fromabout 2 to about 6 carbon atoms. Non-limiting examples of alkynyl groupsinclude ethynyl, propynyl, 2-butynyl and 3-methylbutynyl. An alkynylgroup may be unsubstituted or substituted by one or more substituentswhich may be the same or different, each substituent being independentlyselected from the group consisting of halo, alkenyl, alkynyl, aryl,cycloalkyl, cyano, hydroxy, —O-alkyl, —O-aryl, -alkylene-O-alkyl,alkylthio, —NH₂, —NH(alkyl), —N(alkyl)₂, —NH(cycloalkyl), —O—C(O)-alkyl,—O—C(O)-aryl, —O—C(O)-cycloalkyl, —C(O)OH and —C(O)O-alkyl. In oneembodiment, an alkynyl group is unsubstituted.

The term “alkylene,” as used herein, refers to an alkyl group, asdefined above, wherein one of the alkyl group's hydrogen atoms has beenreplaced with a bond. Non-limiting examples of alkylene groups include—CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, —CH(CH₃)CH₂CH₂—, —CH(CH₃)—and —CH₂CH(CH₃)CH₂—. In one embodiment, an alkylene group has from 1 toabout 6 carbon atoms. In another embodiment, an alkylene group isbranched. In another embodiment, an alkylene group is linear.

The term “aryl,” as used herein, refers to an aromatic monocyclic ormulticyclic ring system comprising from about 6 to about 14 carbonatoms. In one embodiment, an aryl group contains from about 6 to about10 carbon atoms. An aryl group can be optionally substituted with one ormore “ring system substituents” which may be the same or different, andare as defined herein below. Non-limiting examples of aryl groupsinclude phenyl and naphthyl. In one embodiment, an aryl group isunsubstituted. In another embodiment, an aryl group is phenyl.

The term “cycloalkyl,” as used herein, refers to a non-aromatic mono- ormulticyclic ring system comprising from about 3 to about 10 ring carbonatoms. In one embodiment, a cycloalkyl contains from about 5 to about 10ring carbon atoms. In another embodiment, a cycloalkyl contains fromabout 3 to about 7 ring atoms (also referred to herein as“C₃-C₇cycloalkyl”). In another embodiment, a cycloalkyl contains fromabout 5 to about 7 ring atoms. The term “cycloalkyl” also encompasses acycloalkyl group, as defined above, which is fused to an aryl (e.g.,benzene) or heteroaryl ring. Non-limiting examples of monocycliccycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl. Non-limiting examples of multicycliccycloalkyls include 1-decalinyl, norbornyl and adamantyl. A cycloalkylgroup can be optionally substituted with one or more “ring systemsubstituents” which may be the same or different, and are as definedherein below. In one embodiment, a cycloalkyl group is unsubstituted.

The term “cycloalkenyl,” as used herein, refers to a non-aromatic mono-or multicyclic ring system comprising from about 3 to about 10 ringcarbon atoms and containing at least one endocyclic double bond. In oneembodiment, a cycloalkenyl contains from about 5 to about 10 ring carbonatoms. In another embodiment, a cycloalkenyl contains 5 or 6 ring atoms.Non-limiting examples of monocyclic cycloalkenyls include cyclopentenyl,cyclohexenyl, cyclohepta-1,3-dienyl, and the like. A cycloalkenyl groupcan be optionally substituted with one or more “ring systemsubstituents” which may be the same or different, and are as definedherein below. In one embodiment, a cycloalkenyl group is unsubstituted.In another embodiment, a cycloalkenyl group is a 6-memberedcycloalkenyl. In another embodiment, a cycloalkenyl group is a5-membered cycloalkenyl.

The term “heteroaryl,” as used herein, refers to an aromatic monocyclicor multicyclic ring system comprising about 5 to about 14 ring atoms,wherein from 1 to 4 of the ring atoms is independently O, N or S and theremaining ring atoms are carbon atoms. In one embodiment, a heteroarylgroup has 5 to 10 ring atoms. In another embodiment, a heteroaryl groupis monocyclic and has 5 or 6 ring atoms. A heteroaryl group can beoptionally substituted by one or more “ring system substituents” whichmay be the same or different, and are as defined herein below. Aheteroaryl group is joined via a ring carbon atom, and any nitrogen atomof a heteroaryl can be optionally oxidized to the corresponding N-oxide.The term “heteroaryl” also encompasses a heteroaryl group, as definedabove, which is fused to a benzene ring. Non-limiting examples ofheteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl,pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl,oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, triazolyl,1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl,oxindolyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl,benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl,quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, benzothiazolyl and the like. The term “heteroaryl” alsorefers to partially saturated heteroaryl moieties such as, for example,tetrahydroisoquinolyl, tetrahydroquinolyl and the like. In oneembodiment, a heteroaryl group is unsubstituted. In another embodiment,a heteroaryl group is a 5-membered heteroaryl. In another embodiment, aheteroaryl group is a 6-membered heteroaryl.

The term “heterocycloalkyl,” as used herein, refers to a non-aromaticsaturated monocyclic or multicyclic ring system comprising 3 to about 10ring atoms, wherein from 1 to 4 of the ring atoms are independently O, Sor N and the remainder of the ring atoms are carbon atoms. In oneembodiment, a heterocycloalkyl group has from about 5 to about 10 ringatoms. In another embodiment, a heterocycloalkyl group has 5 or 6 ringatoms. There are no adjacent oxygen and/or sulfur atoms present in thering system. Any —NH group in a heterocycloalkyl ring may existprotected such as, for example, as an —N(BOC), —N(Cbz), —N(Tos) groupand the like; such protected heterocycloalkyl groups are considered partof this invention. The term “heterocycloalkyl” also encompasses aheterocycloalkyl group, as defined above, which is fused to an aryl(e.g., benzene) or heteroaryl ring. A heterocycloalkyl group can beoptionally substituted by one or more “ring system substituents” whichmay be the same or different, and are as defined herein below. Thenitrogen or sulfur atom of the heterocycloalkyl can be optionallyoxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.Non-limiting examples of monocyclic heterocycloalkyl rings includepiperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl,thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl,lactam, lactone, and the like. A ring carbon atom of a heterocycloalkylgroup may be functionalized as a carbonyl group. An illustrative exampleof such a heterocycloalkyl group is pyrrolidonyl:

In one embodiment, a heterocycloalkyl group is unsubstituted. In anotherembodiment, a heterocycloalkyl group is a 5-membered heterocycloalkyl.In another embodiment, a heterocycloalkyl group is a 6-memberedheterocycloalkyl.

The term “heterocycloalkenyl,” as used herein, refers to aheterocycloalkyl group, as defined above, wherein the heterocycloalkylgroup contains from 3 to 10 ring atoms, and at least one endocycliccarbon-carbon or carbon-nitrogen double bond. In one embodiment, aheterocycloalkenyl group has from 5 to 10 ring atoms. In anotherembodiment, a heterocycloalkenyl group is monocyclic and has 5 or 6 ringatoms. A heterocycloalkenyl group can optionally substituted by one ormore ring system substituents, wherein “ring system substituent” is asdefined above. The nitrogen or sulfur atom of the heterocycloalkenyl canbe optionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Non-limiting examples of heterocycloalkenyl groups include1,2,3,4-tetrahydropyridinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl,1,2,3,6-tetrahydropyridinyl, 1,4,5,6-tetrahydropyrimidinyl,2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl,dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl,dihydrothiazolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl,fluoro-substituted dihydrofuranyl, 7-oxabicyclo[2.2.1]heptenyl,dihydrothiophenyl, dihydrothiopyranyl, and the like. A ring carbon atomof a heterocycloalkenyl group may be functionalized as a carbonyl group.An illustrative example of such a heterocycloalkenyl group is:

In one embodiment, a heterocycloalkenyl group is unsubstituted. Inanother embodiment, a heterocycloalkenyl group is a 6-memberedheterocycloalkenyl. In another embodiment, a heterocycloalkenyl group isa 5-membered heterocycloalkenyl.

The term “ring system substituent,” as used herein, refers to asubstituent group attached to an aromatic or non-aromatic ring systemwhich, for example, replaces an available hydrogen on the ring system.Ring system substituents may be the same or different, each beingindependently selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, heteroaryl, -alkyl-aryl, -aryl-alkyl,-alkylene-heteroaryl, alkenylene-heteroaryl, -alkynylene-heteroaryl,hydroxy, hydroxyalkyl, haloalkyl, —O-alkyl, —O-haloalkyl,-alkylene-O-alkyl, —O-aryl, aralkoxy, acyl, aroyl, halo, nitro, cyano,carboxy, —C(O)O-alkyl, —C(O)O-aryl, —C(O)O-alkelene-aryl, —S(O)-alkyl,—S(O)₂-alkyl, —S(O)-aryl, —S(O)₂-aryl, —S(O)-heteroaryl,—S(O)₂-heteroaryl, —S-alkyl, —S-aryl, —S-heteroaryl, —S-alkylene-aryl,—-S-alkylene-heteroaryl, cycloalkyl, heterocycloalkyl, —O—C(O)-alkyl,—O—C(O)-aryl, —O—C(O)-cycloalkyl, —C(═N—CN)—N H₂, —C(═NH)—NH₂,—C(═NH)—NH(alkyl), Y₁Y₂N—, Y₁Y₂NC(O)—, Y₁Y₂NS(O)₂— and —S(O)₂NY₁Y₂,wherein Y₁ and Y₂ can be the same or different and are independentlyselected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl,and -alkylene-aryl. “Ring system substituent” may also mean a singlemoiety which simultaneously replaces two available hydrogens on twoadjacent carbon atoms (one H on each carbon) on a ring system. Examplesof such moiety are methylenedioxy, ethylenedioxy, —C(CH₃)₂— and the likewhich form moieties such as, for example:

“Halo” means —F, —Cl, —Br or —I. In one embodiment, halo refers to —F,—Cl or —Br.

The term “haloalkyl,” as used herein, refers to an alkyl group asdefined above, wherein one or more of the alkyl group's hydrogen atomshas been replaced with a halogen. In one embodiment, a haloalkyl grouphas from 1 to 6 carbon atoms. In another embodiment, a haloalkyl groupis substituted with from 1 to 3 F atoms. Non-limiting examples ofhaloalkyl groups include —CH₂F, —CHF₂, —CF₃, —CH₂Cl and —CCl₃.

The term “hydroxyalkyl,” as used herein, refers to an alkyl group asdefined above, wherein one or more of the alkyl group's hydrogen atomshas been replaced with an —OH group. In one embodiment, a hydroxyalkylgroup has from 1 to 6 carbon atoms. Non-limiting examples ofhydroxyalkyl groups include —CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH and—CH₂CH(OH)CH₃.

The term “alkoxy” as used herein, refers to an —O-alkyl group, whereinan alkyl group is as defined above. Non-limiting examples of alkoxygroups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy andt-butoxy. An alkoxy group is bonded via its oxygen atom.

The term “substituted” means that one or more hydrogens on thedesignated atom is replaced with a selection from the indicated group,provided that the designated atom's normal valency under the existingcircumstances is not exceeded, and that the substitution results in astable compound. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds. By“stable compound' or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

The term “purified”, “in purified form” or “in isolated and purifiedform” for a compound refers to the physical state of the compound afterbeing isolated from a synthetic process (e.g. from a reaction mixture),or natural source or combination thereof. Thus, the term “purified”, “inpurified form” or “in isolated and purified form” for a compound refersto the physical state of the compound after being obtained from apurification process or processes described herein or well known to theskilled artisan (e.g., chromatography, recrystallization and the like),in sufficient purity to be characterizable by standard analyticaltechniques described herein or well known to the skilled artisan.

It should also be noted that any carbon as well as heteroatom withunsatisfied valences in the text, schemes, examples and Tables herein isassumed to have the sufficient number of hydrogen atom(s) to satisfy thevalences.

When a functional group in a compound is termed “protected”, this meansthat the group is in modified form to preclude undesired side reactionsat the protected site when the compound is subjected to a reaction.Suitable protecting groups will be recognized by those with ordinaryskill in the art as well as by reference to standard textbooks such as,for example, T. W. Greene et al, Protective Groups in Organic Synthesis(1991), Wiley, New York.

When any variable (e.g., aryl, heterocycle, R², etc.) occurs more thanone time in any constituent or in Formula (I), its definition on eachoccurrence is independent of its definition at every other occurrence.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. A discussion of prodrugs is provided in T. Higuchiand V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of theA.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design,(1987) Edward B. Roche, ed., American Pharmaceutical Association andPergamon Press. The term “prodrug” means a compound (e.g, a drugprecursor) that is transformed in vivo to yield a Substituted BiarylDerivative or a pharmaceutically acceptable salt, hydrate or solvate ofthe compound. The transformation may occur by various mechanisms (e.g.,by metabolic or chemical processes), such as, for example, throughhydrolysis in blood. A discussion of the use of prodrugs is provided byT. Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14of the A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987.

For example, if a Substituted Biaryl Derivative or a pharmaceuticallyacceptable salt, hydrate or solvate of the compound contains acarboxylic acid functional group, a prodrug can comprise an ester formedby the replacement of the hydrogen atom of the acid group with a groupsuch as, for example, (C₁-C₈)alkyl, (C₂-C₁₂)alkanoyloxymethyl,1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms,1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl, and the like.

Similarly, if a Substituted Biaryl Derivative contains an alcoholfunctional group, a prodrug can be formed by the replacement of thehydrogen atom of the alcohol group with a group such as, for example,(C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl,N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkyl, α-amino(C₁-C₄)alkylene-aryl, arylacyl andα-aminoacyl, or α-aminoacyl-α-aminoacyl, where each α-aminoacyl group isindependently selected from the naturally occurring L-amino acids,P(O)(OH)₂, -P(O)(O)(C₁-C₆)alkyl)₂ or glycosyl (the radical resultingfrom the removal of a hydroxyl group of the hemiacetal form of acarbohydrate), and the like.

If a Substituted Biaryl Derivative incorporates an amine functionalgroup, a prodrug can be formed by the replacement of a hydrogen atom inthe amine group with a group such as, for example, R-carbonyl,RO-carbonyl, NRR′-carbonyl where R and R′ are each independently(C₁-C₁₀)alkyl, (C₃-C₇) cycloalkyl, benzyl, or R-carbonyl is a naturalα-aminoacyl, —C(OH)C(O)OY¹ wherein Y¹ is H, (C₁-C₆)alkyl or benzyl,—C(OY²)Y³ wherein Y² is (C₁-C₄) alkyl and Y³ is (C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, amino(C₁-C₄)alkyl or mono-N— ordi-N,N—(C₁-C₆)alkylaminoalkyl, —C(Y⁴)Y⁵ wherein Y⁴ is H or methyl and Y⁵is mono-N— or di-N,N—(C₁-C₆)alkylamino morpholino, piperidin-1-yl orpyrrolidin-1-yl, and the like.

One or more compounds of the invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms. “Solvate” means a physicalassociation of a compound of this invention with one or more solventmolecules. This physical association involves varying degrees of ionicand covalent bonding, including hydrogen bonding. In certain instancesthe solvate will be capable of isolation, for example when one or moresolvent molecules are incorporated in the crystal lattice of thecrystalline solid. “Solvate” encompasses both solution-phase andisolatable solvates. Non-limiting examples of solvates includeethanolates, methanolates, and the like. A “hydrate” is a solvatewherein the solvent molecule is H₂O.

One or more compounds of the invention may optionally be converted to asolvate. Preparation of solvates is generally known. Thus, for example,M. Caira at al, J. Pharmaceutical Sci., 93(3), 601-611 (2004) describethe preparation of the solvates of the antifungal fluconazole in ethylacetate as well as from water. Similar preparations of solvates,hemisolvate, hydrates and the like are described by E. C. van Tonder etal, AAPS PharmSciTechours., 5(1), article 12 (2004); and A. L. Binghamet al, Chem. Commun., 603-604 (2001). A typical, non-limiting, processinvolves dissolving the inventive compound in desired amounts of thedesired solvent (organic or water or mixtures thereof) at a higher thanambient temperature, and cooling the solution at a rate sufficient toform crystals which are then isolated by standard methods. Analyticaltechniques such as, for example I. R. spectroscopy, show the presence ofthe solvent (or water) in the crystals as a solvate (or hydrate).

The Substituted Biaryl Derivatives can form salts which are also withinthe scope of this invention. Reference to a Substituted BiarylDerivative herein is understood to include reference to salts thereof,unless otherwise indicated. The term “salt(s)”, as employed herein,denotes acidic salts formed with inorganic and/or organic acids, as wellas basic salts formed with inorganic and/or organic bases. In addition,when a Substituted Biaryl Derivative contains both a basic moiety, suchas, but not limited to a pyridine or imidazole, and an acidic moiety,such as, but not limited to a carboxylic acid, zwitterions (“innersalts”) may be formed and are included within the term “salt(s)” as usedherein. In one embodiment, the salt is a pharmaceutically acceptable(Le., non-toxic, physiologically acceptable) salt. In anotherembodiment, the salt is other than a pharmaceutically acceptable salt.Salts of the compounds of the Formula (I) may be formed, for example, byreacting a Substituted Biaryl Derivative with an amount of acid or base,such as an equivalent amount, in a medium such as one in which the saltprecipitates or in an aqueous medium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, fumarates, hydrochlorides,hydrobromides, hydroiodides, lactates, maleates, methanesulfonates,naphthalenesulfonates, nitrates, oxalates, phosphates, propionates,salicylates, succinates, sulfates, tartarates, thiocyanates,toluenesulfonates (also known as tosylates,) and the like. Additionally,acids which are generally considered suitable for the formation ofpharmaceutically useful salts from basic pharmaceutical compounds arediscussed, for example, by P. Stahl at al, Camille G. (eds.) Handbook ofPharmaceutical Salts. Properties, Selection and Use. (2002) Zurich:Wiley-VCH; S. Berge at al, Journal of Pharmaceutical Sciences (1977)66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al, The Practice of Medicinal Chemistry (1996),Academic Press, New York; and in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website). These disclosuresare incorporated herein by reference thereto.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as dicyclohexylamine, choline, t-butyl amine, andsalts with amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides andiodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g., decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g., benzyl andphenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

Pharmaceutically acceptable esters of the present compounds include thefollowing groups: (1) carboxylic acid esters obtained by esterificationof the hydroxy group of a hydroxyl compound, in which the non-carbonylmoiety of the carboxylic acid portion of the ester grouping is selectedfrom straight or branched chain alkyl (for example, methyl, ethyl,n-propyl, isopropyl, t-butyl, sec-butyl or n-butyl), alkoxyalkyl (forexample, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl(for example, phenoxymethyl), aryl (for example, phenyl optionallysubstituted with, for example, halogen, C₁₋₄alkyl, or C₁₋₄alkoxy oramino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (forexample, methanesulfonyl); (3) amino acid esters (for example, L-valylor L-isoleucyl); (4) phosphonate esters and (5) mono-, di- ortriphosphate esters. The phosphate esters may be further esterified by,for example, a C₁₋₂₀ alcohol or reactive derivative thereof, or by a2,3-di (C₆₋₂₄)acyl glycerol.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereomers to the corresponding pure enantiomers.Sterochemically pure compounds may also be prepared by using chiralstarting materials or by employing salt resolution techniques. Also,some of the Substituted Biaryl Derivatives may be atropisomers (e.g.,substituted biaryls) and are considered as part of this invention.Enantiomers can also be separated by use of chiral HPLC column.

It is also possible that the Substituted Biaryl Derivatives may exist indifferent tautomeric forms, and all such forms are embraced within thescope of the invention. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the invention.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates, hydrates, esters and prodrugs of the compounds as well as thesalts, solvates and esters of the prodrugs), such as those which mayexist due to asymmetric carbons on various substituents, includingenantiomeric forms (which may exist even in the absence of asymmetriccarbons), rotameric forms, atropisomers, and diastereomeric forms, arecontemplated within the scope of this invention, as are positionalisomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example,if a Substituted Biaryl Derivative incorporates a double bond or a fusedring, both the cis- and trans-forms, as well as mixtures, are embracedwithin the scope of the invention. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the invention).

Individual stereoisomers of the compounds of the invention may, forexample, be substantially free of other isomers, or may be admixed, forexample, as racemates or with all other, or other selected,stereoisomers. The chiral centers of the present invention can have theS or R configuration as defined by the IUPAC 1974 Recommendations. Theuse of the terms “salt”, “solvate”, “ester”, “prodrug” and the like, isintended to apply equally to the salt, solvate, ester and prodrug ofenantiomers, stereoisomers, rotamers, tautomers, positional isomers,racemates or prodrugs of the inventive compounds.

The present invention also embraces isotopically-labelled compounds ofthe present invention which are identical to those recited herein, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ²H, ³H,¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.

Certain isotopically-labelled Substituted Biaryl Derivatives of thepresent invention (e.g., those labeled with ³H and ¹⁴C) are useful incompound and/or substrate tissue distribution assays. In one embodiment,tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C) isotopes are employed fortheir ease of preparation and detectability. In another embodiment,substitution with heavier isotopes such as deuterium (i.e., ²H) mayafford certain therapeutic advantages resulting from greater metabolicstability (e.g., increased in vivo half-life or reduced dosagerequirements). In one embodiment, one or more hydrogen atoms of aSubstituted Biaryl Derivative of the present invention is replaced by adeuterium atom. Isotopically labelled Substituted Biaryl Derivatives ofthe present invention can generally be prepared by following proceduresanalogous to those disclosed in the Schemes and/or in the Examplesherein below, by substituting an appropriate isotopically labelledreagent for a non-isotopically labelled reagent.

Polymorphic forms of the Substituted Biaryl Derivatives, and of thesalts, solvates, hydrates, esters and prodrugs of the Substituted BiarylDerivatives, are intended to be included in the present invention.

The following abbreviations are used herein and have the followingmeanings: BF₃.OEt₂ is boron trifluoride etherate, Boc or BOC is—C(O)O-(t-butyl), DCM is dichloromethane, DME is 1,2-dimethoxyethane,DMEM is Dulbecco's modified eagle medium, DMF is N,N-dimethylformamide,DMSO is dimethylsulfoxide, EtOAc is ethyl acetate, Et₃N istriethylamine, HEPES is (4-(2-hydroxyethyl)-1-piperazineethanesulfonicacid), K^(t)BuO is potatsium tert butoxide, MeOH is methanol, Na^(t)BuOis sodium tert butoxide, NMR is nuclear magnetic resonance, Pd[(Ph)₃P]₄is tetrakis(triphenylphosphine)palladium(0), Ph is phenyl,[(Ph)₃P]₂PdCl₂ is bis(triphenylphosphine)palladium(II) chloride,Ph₃MeP⁺Br⁻ is (methyl)triphenylphosphonium bromide, RT is roomtemperature, TFA is trifluoroacetic acid and TLC is thin-layerchromatography.

The Substituted Biaryl Derivatives of Formula (I)

The present invention provides Substituted Biaryl Derivatives of Formula(I):

and pharmaceutically acceptable salts, solvates, esters, prodrugs andstereoisomers thereof, wherein A, B, Q, W, X, Y, Z, R¹, R², R³, R⁷, p,q, r, s and u are defined above for the Compounds of Formula (I).

In one embodiment, A is:

In another embodiment, A is:

In another embodiment, A is:

In one embodiment, B is other than phenyl.

In another embodiment, B is:

In another embodiment, B is:

In one embodiment, A is:

and B is:

In one embodiment, Q is —O—.

In another embodiment, Q is —NH—.

In another embodiment, Q is —N(R¹⁵)—.

In still another embodiment, Q is —S(O)₂—.

In one embodiment, W is a bond.

In another embodiment, W is alkylene.

In another embodiment, W is —C(O)—.

In still another embodiment, W is —C(O)O—.

In another embodiment, W is —S(O)₂—.

In another embodiment, W is —NH—.

In yet another embodiment, W is a bond, —C(O)O— or —S(O)₂—.

In another embodiment, W is a bond or —C(O)O—.

In one embodiment, W is —C(O)O— and R³ is alkyl, cycloalkyl orheteroaryl, wherein a cycloalkyl or heteroaryl group can be optionallysubstituted with alkyl.

In another embodiment, W is a bond and R³ is heteroaryl, which can beoptionally substituted with alkyl.

In one embodiment, X is —S(O)₂R¹⁵.

In another embodiment, X is —S(O)₂CH₃.

In another embodiment, X is halo.

In still another embodiment, X is —CF₃.

In another embodiment, X is —CN.

In yet another embodiment, X is —OH.

In another embodiment, X is aryl.

In a further embodiment, X is phenyl.

In another embodiment, X is 5 or 6 membered heteroaryl.

In one embodiment, Y is a bond.

In another embodiment, Y is C₁-C₃ alkylene.

In another embodiment, Y is —CH₂—.

In one embodiment, Z is —C(R¹)₂—.

In another embodiment, Z is a bond.

In another embodiment, Z is —O—.

In still another embodiment, Z is —S—.

In another embodiment, Z is —CH═CH—.

In another embodiment, Z is —S(O)₂—.

In a further embodiment, Z is —N(R¹⁰)—.

In another embodiment, Z is —CHR¹—.

In another embodiment, Z is —CH₂—.

In still another embodiment, Z is —NH—.

In one embodiment, each occurrence of R¹ is selected from H, halo or—OH.

In another embodiment, each occurrence of R¹ is H.

In another embodiment, at least one occurrence of R¹ is OH.

In still another embodiment, at least one occurrence of R¹ is halo.

In another embodiment, at least one occurrence of R¹ is F.

In another embodiment, at least one occurrence of R² is H or alkyl.

In another embodiment, at least one occurrence of R² is alkyl.

In a further embodiment, at least one occurrence of R² is H.

In another embodiment, each occurrence of R² is H.

In one embodiment, each occurrence of R¹ and R² is H.

In one embodiment, R³ is alkyl.

In another embodiment, R³ is a linear alkyl group.

In another embodiment, R³ is a branched alkyl group.

In still another embodiment, R³ is methyl.

In another embodiment, R³ is ethyl.

In another embodiment, R³ is isopropyl.

In a further embodiment, R³ is t-butyl.

In another embodiment, R³ is alkenyl.

In another embodiment, R³ is alkynyl.

In yet another embodiment, R³ is haloalkyl.

In one embodiment, R³ is cycloalkyl.

In another embodiment, R³ is cyclopropyl.

In another embodiment, R³ is cyclopropyl, substituted with a methylgroup.

In still another embodiment, R³ is 1-methylcyclopropyl.

In another embodiment, R³ is cyclobutyl.

In another embodiment, R³ is cyclopentyl.

In yet another embodiment, R³ is cyclohexyl.

In another embodiment, R³ is aryl.

In another embodiment, R³ is phenyl.

In still another embodiment, R³ is naphthyl.

In another embodiment, R³ is -alkylene-aryl.

In another embodiment, R³ is benzyl.

In one embodiment, R³ is -alkylene-O-alkylene-aryl.

In another embodiment, R³ is pyrimidin-2-yl, which can be optionallysubstituted at the 4-position of the pyrimidine ring.

In another embodiment, R³ is aryl, alkyl, -alkylene-aryl, alkenyl,alkynyl, cycloalkyl, heteroaryl, -alkylene-O-alkylene-aryl or-alkylene-cycloalkyl, wherein a cycloalkyl group can be optionallysubstituted with an alkyl group.

In another embodiment, R³ is alkyl or cycloalkyl, wherein a cycloalkylgroup can be optionally substituted with an alkyl group.

In still another embodiment, R³ is methyl, isopropyl, cyclopropyl orcyclobutyl, wherein a cyclopropyl or cyclobutyl group can be optionallysubstituted with an alkyl group.

In one embodiment, R³ is alkyl, cycloalkyl or heteroaryl, wherein acycloalkyl or heteroaryl group can be optionally substituted with analkyl group.

In another embodiment, R³ is t-butyl, 1-methylcyclopropyl or4-propyl-pyrimidin-2-yl.

In one embodiment, R⁷ is H.

In another embodiment, R⁷ is alkyl.

In one embodiment, R⁸ is H.

In another embodiment, R⁸ is C₃-C₇ cycloalkyl.

In one embodiment, R¹¹ is H.

In another embodiment, R¹¹ is C₃-C₇ cycloalkyl.

In one embodiment, R⁸ and R¹¹ are each H.

In another embodiment, R⁸, R¹¹, and the common carbon atom to which bothare attached, join to form a 3- to 7-membered cycloalkyl group.

In one embodiment, W is —C(O)O— or a bond and R³ is alkyl, cycloalkyl orheteroaryl, wherein a cycloalkyl or heteroaryl group can be optionallysubstituted with an alkyl group.

In another embodiment, W is —C(O)O— and R³ is t-butyl or1-methylcyclopropyl.

In another embodiment, W is a bond and R³ is 4-propyl-pyrimidin-2-yl.

In one embodiment, the group —W—R³ is —S(O)₂-cyclopropyl,—S(O)₂-cyclobutyl, —S(O)₂CF₃, —S(O)₂CH₂CH₂OCH₃, —C(O)O-cyclopropyl,—C(O)O-cyclobutyl, -C(O)O-(1-methylcyclopropyl),—C(O)O-(1-methylcyclobutyl), —C(O)O-(1-methylcyclopropyl),—C(O)O-isopropyl or benzyl.

In one embodiment, the group:

In still another embodiment, the group:

In one embodiment, the group:

In one embodiment, the group:

In one embodiment, W is —C(O)O— and R³ is aryl, -alkylene-aryl, alkyl,alkenyl, alkynyl, cycloalkyl, heteroaryl, -alkylene-O-alkylene-aryl or-alkylene-cycloalkyl.

In another embodiment, W is —C(O)O— and R³ is phenyl, t-butyl,4-bromophenyl, 3-trifluoromethylphenyl, 4-nitrobenzyl,4-(C(O)OCH₃)phenyl, naphthyl, 2-chlorobenzyl, methyl, ethyl, propyl,butyl, pentyl, hexyl, heptyl, octyl, nonyl, 4-chlorophenyl,4-methoxyphenyl, 2-methoxyphenyl, 4-fluorophenyl, benzyl,4-methylphenyl, neopentyl, cyclopentyl, sec-butyl, butynyl, butynyl,propenyl, propynyl, isopropenyl, cyclobutyl, isopropyl,—CH₂-cyclopropyl, —CH(cyclopropyl)(CH₃), —CH(cyclopropanyl)₂ or—CH(CH₃)phenyl.

In another embodiment, W is -S(O)₂- and R³ is aryl, alkyl, heteroaryl,-alkylene-aryl or cycloalkyl.

In still another embodiment, W is —S(O)₂— and R³ is 4-fluorophenyl,methyl, ethyl, propyl, butyl, 5-chloro-thiophenyl, cyclopropyl,4-(NHC(O)CH₃)phenyl, benzyl, 3-chlorobenzyl, 4-chlorobenzyl, sec-butyl,4-methylbenzyl or 2-chlorobenzyl.

In another embodiment, W is —S(O)₂— and R³ is cycloalkyl, haloalkyl or—alkylene-O-alkyl, wherein a cycloalkyl group can be optionallysubstituted with an alkyl group.

In another embodiment, W is —S(O)₂— and R³ is cycloalkyl, which isunsubstituted or optionally substituted with an alkyl group.

In yet another embodiment, W is —S(O)₂— and R³ is cyclopropyl orcyclobutyl, each of which is unsubstituted or optionally substitutedwith an alkyl group.

In a further embodiment, W is —S(O)₂— and R³ is cyclopropyl. In oneembodiment, W is —C(O)O— and R³ is alkyl, cycloalkyl oralkyl-substituted cycloalkyl.

In another embodiment, W is —C(O)O— and R³ is methyl, isopropyl,isobutyl, cyclopropyl, cyclobutyl, methyl-substituted cyclopropyl ormethyl-substituted cyclobutyl.

In another embodiment, W is —S(O)₂— and R³ is haloalkyl,-alkylene-O-alkyl, cycloalkyl or alkyl-substituted cycloalkyl.

In still another embodiment, W is —S(O)₂— and R³ is cyclopropyl,cyclobutyl, trifluoromethyl, —CH₂CH₂OCH₃, methyl-substitutedcyclopropyl, methyl-substituted cyclobutyl.

In one embodiment, W is a bond and R³ is aryl, -alkylene-aryl or alkyl.

In another embodiment, W is a bond and R³ is phenyl.

In another embodiment, W is a bond and R³ is benzyl.

In one embodiment, p and u are each 1.

In another embodiment, u, p, q, r, and s are each independently 0 or 1.

In another embodiment, p and u are each 1, and r and s are each 0.

In another embodiment, p and u are each 0, and r and s are each 1.

In another embodiment, q, p and u are each 1, r and s are each 0 and Zis a bond.

In still another embodiment, q, p and u are each 1, r and s are each 0,Z is a bond, and W is —C(O)O—.

In one embodiment, A is:

B is:

andQ is —O—.

In another embodiment, A is:

B is:

Q is —O—; and Y is a bond.

In another embodiment, A is:

B is:

Q is —O—; Y is a bond; and X is —S(O)₂R¹⁵.

In another embodiment, A is:

B is:

Q is —O—; Y is a bond; X is —S(O)₂R¹⁵; and the group:

In another embodiment, A is:

B is:

Q is —O—; Y is a bond; X is —S(O)₂R¹⁵; and the group:

In another embodiment, A is:

R′ is H or F;B is:

Q is —O—; Y is a bond; X is —S(O)₂CH₃; and the group:

In one embodiment, the present invention provides Compounds of Formula(I), wherein A, B, Q, W, X, Y, Z, R³, R⁶, R^(6a), R⁷, R⁸, R¹¹, p, q, r,s and u, and each occurrence of R¹ and R² are selected independently ofeach other.

In another embodiment, a Compound of Formula (I) is in purified form.

In one embodiment, the Compounds of Formula (I) have the formula:

wherein:

E is:

W is a bond or —C(O)—O—;

R³ is alkyl, cycloalkyl or heteroaryl, wherein a cycloalkyl orheteroaryl group can be unsubstituted or optionally substituted with R⁹;

each occurrence of R⁴ is H, alkyl, cycloalkyl or alkenyl, wherein analkyl group can be optionally substituted with halo, —OH or —O-alkyl;

R⁶ is halo;

R⁹ is alkyl;

R¹⁵ is alkyl; and

each occurrence of m is 0 or 1.

In one embodiment, for the Compounds of Formula (Ia), W is a bond.

In another embodiment, for the Compounds of Formula (Ia), W is —C(O)O—.

In one embodiment, for the Compounds of Formula (Ia), R³ is alkyl.

In another embodiment, for the Compounds of Formula (Ia), R³ is t-butyl.

In another embodiment, for the Compounds of Formula (Ia), R³ iscycloalkyl, which is optionally substituted with alkyl.

In still another embodiment, for the Compounds of Formula (Ia), R³ is1-methylcyclopropyl.

In another embodiment, for the Compounds of Formula (Ia), R³ isheteroaryl.

In still another embodiment, for the Compounds of Formula (Ia), R³ is4-propyl-pyrimidin-2-yl.

In one embodiment, for the Compounds of Formula (Ia), R⁶ is halo.

In another embodiment, for the Compounds of Formula (Ia), R⁶ is F.

In one embodiment, for the Compounds of Formula (Ia), m is 0.

In another embodiment, for the Compounds of Formula (Ia), m is 1.

In another embodiment, for the Compounds of Formula (Ia), m is 1 and R⁶is F.

In one embodiment, for the Compounds of Formula (Ia), R³ is alkyl.

In another embodiment, for the Compounds of Formula (Ia), R³ is t-butyl.

In one embodiment, for the Compounds of Formula (Ia), R¹⁵ is alkyl.

In another embodiment, for the Compounds of Formula (Ia), R¹⁵ is methyl.

In one embodiment, for the Compounds of Formula (Ia), E is:

In one embodiment, for the Compounds of Formula (Ia), E is:

and R¹⁵ is methyl.

In one embodiment, for the Compounds of Formula (Ia), E is:

R¹⁵ is methyl; and m is 0.

In one embodiment, for the Compounds of Formula (Ia), E is:

R¹⁵ is methyl; m is 1; and R⁶ is F.

Non-limiting examples of the Substituted Biaryl Derivatives of Formula(I) include Compounds 1-11, depicted below:

Compound No. Structure 1

2

3

4

5

6

7

8

9

10

11

and pharmaceutically acceptable salts, solvates, esters, prodrugs andstereoisomers thereof.

Methods for Making the Substituted Biaryl Derivatives

Methods useful for making the Substituted Biaryl Derivatives are setforth in the Examples below and generalized in Schemes 1 and 2.Alternative synthetic pathways and analogous structures will be apparentto those skilled in the art of organic synthesis.

Scheme 1 illustrates a method useful for making the Compounds of Formulaiii, which are useful intermediates for making the Substituted BiarylDerivatives.

wherein B, Q, W, Z, R¹, R², R³, R⁷, R⁸, R¹¹, q, p, r, s and u aredefined above for the Compounds of Formula (I) and Hal is —Cl or —Br.

A dichloro aryl or heteroaryl Compound of Formula i can be reacted witha bicyclic Compound of Formula ii in the presence of a non-nucleophilicbase, such as potassium tert-butoxide to provide the intermediateCompounds of Formula iii.

Scheme 2 illustrates a general method useful for making the Compounds ofFormula (I).

wherein A, B, Q, W, X, Y, Z, R¹, R², R³, R⁷, R⁸, R¹¹, r, s and u aredefined above for the Compounds of Formula (1) and Hal is —Cl or —Br.

A Compound of Formula iii can be coupled with a boronic acid couplingpartner of formula iv via a palladium-catalyzed process, such as aSuzuki coupling reaction, to to provide the Compounds of Formula (I).The Compounds of Formula iii can be commercially available or can beprepared using methods well-known to one skilled in the art of organicchemistry.

The starting materials and reagents depicted in Schemes 1 and 2 areeither available from commercial suppliers such as Sigma-Aldrich (St.Louis, Mo.) and Acros Organics Co. (Fair Lawn, N.J.), or can be preparedusing methods well-known to those of skill in the art of organicsynthesis.

One skilled in the art will recognize that the synthesis of SubstitutedBiaryl Derivatives may require the need for the protection of certainfunctional groups (Le., derivatization for the purpose of chemicalcompatibility with a particular reaction condition). Suitable protectinggroups for the various functional groups of the Substituted BiarylDerivatives and methods for their installation and removal may be foundin Greene et al., Protective Groups in Organic Synthesis,Wiley-Interscience, New York, (1999).

EXAMPLES

The following examples exemplify illustrative examples of compounds ofthe present invention and are not to be construed as limiting the scopeof the disclosure. Alternative mechanistic pathways and analogousstructures within the scope of the invention may be apparent to thoseskilled in the art.

General Methods

Solvents, reagents, and intermediates that are commercially availablewere used as received. Reagents and intermediates that are notcommercially available were prepared in the manner described below. ¹HNMR spectra were obtained on a Gemini AS-400 (400 MHz) and are reportedas ppm down field from Me₄Si with number of protons, multiplicities, andcoupling constants in Hertz indicated parenthetically. Where LC/MS dataare presented, analyses was performed using an Applied BiosystemsAPI-100 mass spectrometer and Shimadzu SCL-10A LC column: Altechplatinum C18, 3 micron, 33 mm×7mm ID; gradient flow: 0 min-10% CH₃CN, 5min-95% CH₃CN, 7 min-95% CH₃CN, 7.5 min-10% CH₃CN, 9 min-stop. Theobserved parent ions are given.

Example 1 Preparation of Intermediate Compound 1C

Compound 1C (2.63 g, 79%) was prepared from commercially available N-Bocnortropinone (1A) (Chem-Impex International) using the methods describedin International Publication No. WO 04/100946, and was used withoutfurther purification.

Example 2 Preparation of Intermediate Compound 2C

A solution of compound 2A (635 mg, 2.63 mmol) and sodium t-butoxide (252mg, 2,63 mmol) in THF (10 mL) was stirred for 15 minutes at roomtemperature. 5-bromo-2-chloropyrimidine (2B) (425 mg, 2.19 mmol) wasthen added and the reaction was heated to 60° C. and allowed to stir atthis temperature for 17 hours, then the reaction mixture was cooled toroom temperature and concentrated in vacuo. The resulting residue wastaken up in EtOAc and washed with water. The organic phase wasseparated, dried over MgSO₄, filtered and concentrated in vacuo and theresulting residue was purified using flash column chromatography (40 gsilica cartridge, 0-25% EtOAc/Hexanes) to provide compound 2C (191 mg,29%). M+H=398

Example 3 Preparation of Compound 1

A solution of Compound 2C (250 mg, 0.63 mmol), 4-methylsulfonylphenylboronic acid (155 mg, 0.77 mmol), potassium carbonate (353 mg, 2.55mmol), and tetrakis(triphenylphosphine)palladium(0) (17 mg) in dioxane(3.5 mL) and water (0.4 mL) was placed in a sealed tube, heated to 90°C. and allowed to stand at this temperature for 24 hours. The reactionmixture was cooled to room temperature and concentrated in vacuo. Theresulting residue was taken up in EtOAc, washed sequentially with waterand 1 N NaOH, dried over MgSO₄, then filtered and concentrated in vacuo.The resulting residue was purified using preparative TLC (5% MeOH/DCM)to provide compound 1 (135 mg, 45%). M+H=474

Example 4 Preparation of Compound 4

Step A—Synthesis of Compound 4A

A solution of compound 1 (115 mg, 0.24 mmol) in DCM (10 mL) was placedunder nitrogen atmosphere and trifluoroacetic acid (0.3 mL) was added.The resulting reaction was allowed to stir for 18 hours, then wasquenched with saturated aqueous NaHCO₃ solution and extracted with DCM.The organic layer was dried over MgSO₄, filtered and concentrated invacuo to provide compound 4A (66.5 mg, 74%) which was used withoutfurther purification.

Step B—Synthesis of Compound 4

To a solution of compound 4A (30 mg, 0.06 mmol) in DCM (2 mL) was addedtriethylamine (0.02 mL, 0.17 mmol), followed by compound 8 (35 mg, 0.12mmol). The reaction was placed under nitrogen atmosphere and allowed tostir at room temperature for 20 hours, then was quenched with saturatedaqueous NH₄Cl solution and extracted with DCM. The organic layer wasdried over MgSO₄, filtered and concentrated in vacuo and the resultingresidue was purified using preparative TLC (4% MeOH/DCM, run 2 times) toprovide compound 4 (24 mg, 63%). M+H=494

Example 5 Preparation of Compound 7

To a stirred suspension of compound 4A (31 mg, 0.083 mmol) and potassiumcarbonate (48 mg, 0.35 mmol) in DMF (2 mL) was added 2-chloro-5-phenylpyrimidine (20 mg, 0.13 mmol). The reaction was placed in a sealed tube,heated to 100° C. and allowed to stand at this temperature for 16 hours.The reaction mixture was then cooled to room temperature, then dilutedwith water (3 mL) and EtOAc (3 mL). The organic layer was separated,dried over MgSO₄, filtered and concentrated in vacuo and the resultingresidue was purified using preparative TLC (4% MeOH/DCM) to providecompound 7 (6 mg, 15%). M+H=494

Example 6 Preparation of Compound 2

A solution of Compound 2C (250 mg, 0.63 mmol),2-fluoro-4-(methylsulfonyl)phenyl boronic acid (139 mg, 0.64 mmol), 2 Msodium carbonate (3.2 mL, 6.30 mmol), andbis(triphenylphosphine)palladium(II) dichloride (22 mg) in DME (3.7 mL)was placed in a sealed tube, heated to 100° C., and allowed to stir atthis temperature for 24 hours. The reaction mixture was then cooled toroom temperature and diluted with EtOAc (5 mL) and water (5 mL). Theresulting mixture was filtered through celite and the filtrate wasextracted with EtOAc. The organic layer was dried over MgSO₄, filteredand concentrated in vacuo and the residue obtained was purified usingpreparative TLC (5% MeOH/DCM) then washed with acetonitrile to providecompound 2 (108 mg, 35%). M+Na=514

Example 7 Preparation of Compound 5

Step A—Synthesis of Compound 7A

Compound 7A (56 mg, 100%) was prepared from Compound 2 (70 mg, 0.14mmol) using the method described in Example 4, Step A, and used withoutfurther purification.

Step B—Synthesis of Compound 5

Compound 7A (28 mg, 0.072 mmol) was converted to Compound 5 (10 mg, 29%)using the method described in Example 4, Step B. M+H=490

Example 8 Preparation of Compound 3

Compound 7A (28 mg, 0.072 mmol) was converted to Compound 3 (3 mg, 8%)using the method described in Example 5. M+H=512

Example 9 Preparation of Intermediate Compound 9C

Compound 9A (prepared as described in Waldmann et al., Chem. Eur. J.(2002), 8:4761) was converted to compound 9C (98% yield) using themethod described in Example 1.

Example 10 Preparation of Intermediate Compound 10B

5-Bromo-2-chloropyrimidine (2A) (610 mg, 3.15 mmol) was reacted withcompound 9C (800 mg, 3.11 mmol) using the method described in Example 2to provide Compound 10A as a mixture of isomers. This mixture of isomerswas purified using flash chromatography (100 g spherical cartridge,0-50% EtOAc/Hexanes) to provide the syn isomer 10B (150 mg, 12%) plus amixture of isomers 10A (330 mg, 26%).

Example 11 Preparation of Compound 10

Compound 10B (136 mg, 0.33 mmol) was reacted with2-fluoro-4-(methylsulfonyl)phenyl boronic acid (72 mg, 0.33 mmol) usingthe method described in Example 6 to provide compound 10 (82 mg, 49%).M+H=508

Example 12 Preparation of Compound 8

Step A—Synthesis of Compound 12A

Compound 10 (72 mg, 0.14 mmol) was deprotected using the methoddescribed in Example 4, Step A, to provide compound 12A (58 mg, 100%)which was used without further purification.

Step B—Synthesis of Compound 8

Compound 12A (24 mg, 0.059 mmol) was converted to Compound 8 (10 mg,29%) using the method described in Example 4, Step B. M+H=506

Example 13 Preparation of Compound 6

Compound 12A (30 mg, 0.0742 mmol) was converted to Compound 6 (16 mg,41%) using the method described in Example 6. M+H=528

Example 14 Preparation of Compounds 9 and 11

Compound 10A (330 mg, 0.80 mmol) was reacted with2-fluoro-4-(methylsulfonyl)phenyl boronic acid (175 mg, 0.80 mmol) usingthe method described in Example 7 to provide Compound 11 Compound 11 wassubsequently purified using flash chromatography (23 g silica cartridge,0-5% MeOH/DCM) to provide Compound 9 (anti isomer, 34 mg, 8%). M+H=508

Example 18 cAMP Assay

The ability of illustrative compounds of the invention to activateGPR119 and stimulate increases in cAMP levels was determined using theLANCE™ cAMP kit (Perkin Elmer). HEK293 cells expressing human GPR119were maintained in culture flasks at 37° C./5% CO₂ in DMEM containing10% fetal bovine serum, 100 U/ml Pen/Strep, and 0.5 mg/ml geneticin. Themedia was changed to Optimem and cells were incubated overnight at 37°C./5% CO₂. The Optimem was then aspirated and the cells were removedfrom the flasks using room temperature Hank's balanced saline solution(HBSS). The cells were pelleted using centrifugation (1300 rpm, 7minutes, room temperature), then resuspended in stimulation buffer(HBSS, 0.1% BSA, 5 mM HEPES, 15 μM RO-20) at 2.5×10⁶ cells/mL. AlexaFluor 647-anti cAMP antibody (1:100) was then added to the cellsuspension and incubated for 30 minutes. A representative SubstitutedBiaryl Derivative (6 μl at 2× concentration) in stimulation buffercontaining 2% DMSO were then added to white 384 well Matrix plates. Cellsuspension mix (6 μl) was added to each well and incubated with theSubstituted Biaryl Derivative for 30 minutes. A cAMP standard curve wasalso created in each assay according to the kit protocol. Standardconcentrations of cAMP in stimulation buffer (6 μl) were added to white384 well plates. Subsequently, 6 μl of 1:100 anti-cAMP antibody wasadded to each well. Following the 30 minute incubation period, 12 μl ofdetection mix (included in kit) was added to all wells and incubated for2-3 hours at room temperature. Fluorescence was detected on the platesusing an Envision instrument. The level of cAMP in each well isdetermined by extrapolation from the cAMP standard curve.

Using this assay, EC₅₀ values for various illustrative SubstitutedBiaryl Derivatives of the present invention were calculated and rangefrom about 70 nM to about 0.5 μM.

Example 19 Effect of the Compounds of the Invention in Oral GlucoseTolerance Test

Male C57BI/6NCrl mice (6-8 week old) are fasted overnight and randomlydosed with either vehicle (such as 20% hydroxypropyl-β-cyclodextrin) ora representative test compound (at 3, 10 or 30 mg/kg) via oral gavage.Glucose is then administered to the animals 30 minutes post-dosing (3g/kg p.o.). Blood glucose levels are to be measured prior toadministration of test compound and glucose, then at 20 minutes afterglucose administration using, for example, a hand-held glucometer (suchas the Ascensia Elite, Bayer).

Uses of the Substituted Biaryl Derivatives

The Substituted Biaryl Derivatives are useful in human and veterinarymedicine for treating or preventing a Condition in a patient. Inaccordance with the invention, the Substituted Biaryl Derivatives can beadministered to a patient in need of treatment or prevention of aCondition.

Treatment of Obesity and Obesity-Related Disorders

The Substituted Biaryl Derivatives are useful for treating obesity or anobesity-related disorder.

Accordingly, in one embodiment, the invention provides methods fortreating obesity or an obesity-related disorder in a patient, whereinthe method comprises administering to the patient an effective amount ofone or more Substituted Biaryl Derivatives, or a pharmaceuticallyacceptable salt, solvate, ester, prodrug or stereoisomer thereof.

Treatment of Diabetes

The Substituted Biaryl Derivatives are useful for treating diabetes in apatient. Accordingly, in one embodiment, the present invention providesa method for treating diabetes in a patient, comprising administering tothe patient an effective amount of one or more Substituted BiarylDerivatives.

Non-limiting examples of diabetes treatable or preventable using theSubstituted Biaryl Derivatives include, type I diabetes(insulin-dependent diabetes mellitus), type II diabetes (non-insulindependent diabetes mellitus), gestational diabetes, autoimmune diabetes,insulinopathies, idiopathic type I diabetes (Type 1b), latentautoimmumne diabetes in adults, early-onset type 2 diabetes (EOD),youth-onset atypical diabetes (YOAD), maturity onset diabetes of theyoung (MODY), malnutrition-related diabetes, diabetes due to pancreaticdisease, diabetes associated with other endocrine diseases (such asCushing's Syndrome, acromegaly, pheochromocytoma, glucagonoma, primaryaldosteronism or somatostatinoma), type A insulin resistance syndrome,type B insulin resistance syndrome, lipatrophic diabetes, diabetesinduced by β-cell toxins, and diabetes induced by drug therapy (such asdiabetes induced by antipsychotic agents).

In one embodiment, the diabetes is type I diabetes.

In another embodiment, the diabetes is type II diabetes.

Treatment of a Diabetic Complication

The Substituted Biaryl Derivatives are useful for treating a diabeticcomplication in a patient. Accordingly, in one embodiment, the presentinvention provides a method for treating a diabetic complication in apatient, comprising administering to the patient an effective amount ofone or more Substituted Biaryl Derivatives.

Non-limiting examples of diabetic complications treatable or preventableusing the Substituted Biaryl Derivatives include diabetic cataract,glaucoma, retinopathy, aneuropathy (such as diabetic neuropathy,polyneuropathy, mononeuropathy, autonomic neuropathy, microaluminuriaand progressive diabetic neuropathyl), nephropathy, gangrene of thefeet, immune-complex vasculitis, systemic lupsus erythematosus (SLE),atherosclerotic coronary arterial disease, peripheral arterial disease,nonketotic hyperglycemic-hyperosmolar coma, foot ulcers, joint problems,a skin or mucous membrane complication (such as an infection, a shinspot, a candidal infection or necrobiosis lipoidicadiabeticorumobesity), hyperlipidemia, cataract, hypertension, syndromeof insulin resistance, coronary artery disease, a fungal infection, abacterial infection, and cardiomyopathy.

Treatment of a Metabolic Disorder

The Substituted Biaryl Derivatives are useful for treating a metabolicdisorder. Accordingly, in one embodiment, the invention provides methodsfor treating a metabolic disorder in a patient, wherein the methodcomprises administering to the patient an effective amount of one ormore Substituted Biaryl Derivatives, or a pharmaceutically acceptablesalt, solvate, ester, prodrug or stereoisomer thereof.

Non-limiting examples of metabolic disorders treatable include metabolicsyndrome (also known as “Syndrome X”), impaired glucose tolerance,impaired fasting glucose, hypercholesterolemia, hyperlipidemia,hypertriglyceridemia, low HDL levels, hypertension, phenylketonuria,post-prandial lipidemia, a glycogen-storage disease, Gaucher's Disease,Tay-Sachs Disease, Niemann-Pick Disease, ketosis and acidosis.

In one embodiment, the metabolic disorder is hypercholesterolemia.

In another embodiment, the metabolic disorder is hyperlipidemia.

In another embodiment, the metabolic disorder is hypertriglyceridemia.

In still another embodiment, the metabolic disorder is metabolicsyndrome.

In a further embodiment, the metabolic disorder is low HDL levels.

Methods for Treating a Cardiovascular Disease

The Substituted Biaryl Derivatives are useful for treating or preventinga cardiovascular disease in a patient. Accordingly, in one embodiment,the present invention provides a method for treating a cardiovasculardisease in a patient, comprising administering to the patient aneffective amount of one or more Substituted Biaryl Derivatives.

Non-limitng examples of cardiovascular diseases treatable or preventableusing the present methods include atherosclerosis, congestive heartfailure, cardiac arrhythmia, myocardial infarction, atrial fibrillation,atrial flutter, circulatory shock, left ventricular hypertrophy,ventricular tachycardia, supraventricular tachycardia, coronary arterydisease, angina, infective endocarditis, non-infective endocarditis,cardiomyopathy, peripheral artery disease, Reynaud's phenomenon, deepvenous thrombosis, aortic stenosis, mitral stenosis, pulmonic stenosisand tricuspid stenosis.

In one embodiment, the cardiovascular disease is atherosclerosis.

In another embodiment, the cardiovascular disease is congestive heartfailure.

In another embodiment, the cardiovascular disease is coronary arterydisease.

Combination Therapy

In one embodiment, the present invention provides methods for treating aCondition in a patient, the method comprising administering to thepatient one or more Substituted Biaryl Derivatives, or apharmaceutically acceptable salt, solvate, ester, prodrug orstereoisomer thereof and at least one additional therapeutic agent thatis not a Substituted Biaryl Derivative, wherein the amounts administeredare together effective to treat or prevent a Condition.

Non-limiting examples of additional therapeutic agents useful in thepresent methods for treating or preventing a Condition include,anti-obesity agents, antidiabetic agents, any agent useful for treatingmetabolic syndrome, any agent useful for treating a cardiovasculardisease, cholesterol biosynthesis inhibitors, cholesterol absorptioninhibitors, bile acid sequestrants, probucol derivatives, IBATinhibitors, nicotinic acid receptor (NAR) agonists, ACAT inhibitors,cholesteryl ester transfer proten (CETP) inhibitors, low-denisitylipoprotein (LDL) activators, fish oil, water-soluble fibers, plantsterols, plant stanols, fatty acid esters of plant stanols, or anycombination of two or more of these additional therapeutic agents.

Non-limiting examples of anti-obesity agents useful in the presentmethods for treating a Condition include CB1 antagonists or inverseagonists such as rimonabant, neuropeptide Y antagonists, MCR4 agonists,MCH receptor antagonists, histamine H₃ receptor antagonists or inverseagonists, metabolic rate enhancers, nutrient absorption inhibitors,leptin, appetite suppressants and lipase inhibitors.

Non-limiting examples of appetite suppressant agents useful in thepresent methods for treating or preventing a Condition includecannabinoid receptor 1 (CB₁) antagonists or inverse agonists (e.g.,rimonabant); Neuropeptide Y (NPY1, NPY2, NPY4 and NPY5) antagonists;metabotropic glutamate subtype 5 receptor (mGluR5) antagonists (e.g.,2-methyl-6-(phenylethynyl)-pyridine and3[(2-methyl-1,4-thiazol-4-yl)ethynyl]pyridine); melanin-concentratinghormone receptor (MCH1R and MCH2R) antagonists; melanocortin receptoragonists Melanotan-Il and Mc4r agonists); serotonin uptake inhibitors(e.g., dexfenfluramine and fluoxetine); serotonin (5HT) transportinhibitors (e.g., paroxetine, fluoxetine, fenfluramine, fluvoxamine,sertaline and imipramine); norepinephrine (NE) transporter inhibitors(e.g., desipramine, talsupram and nomifensine); ghrelin antagonists;leptin or derivatives thereof; opioid antagonists (e.g., nalmefene,3-methoxynaltrexone, naloxone and nalterxone); orexin antagonists;bombesin receptor subtype 3 (BRS3) agonists; Cholecystokinin-A (CCK-A)agonists; ciliary neurotrophic factor (CNTF) or derivatives thereof(e.g., butabindide and axokine); monoamine reuptake inhibitors (e.g.,sibutramine); glucagon-like peptide 1 (GLP-1) agonists; topiramate; andphytopharm compound 57.

Non-limiting examples of metabolic rate enhancers useful in the presentmethods for treating or preventing a Condition include acetyl-CoAcarboxylase-2 (ACC2) inhibitors; beta adrenergic receptor 3 (β3)agonists; diacylglycerol acyltransferase inhibitors (DGAT1 and DGAT2);fatty acid synthase (FAS) inhibitors (e.g., Cerulenin);phosphodiesterase (PDE) inhibitors (e.g., theophylline, pentoxifylline,zaprinast, sildenafil, amrinone, milrinone, cilostamide, rolipram andcilomilast); thyroid hormone β agonists; uncoupling protein activators(UCP-1,2 or 3) (e.g., phytanic acid,4-[(E)-2-(5,6,7,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acidand retinoic acid); acyl-estrogens (e.g., oleoyl-estrone);glucocorticoid antagonists; 11-beta hydroxy steroid dehydrogenase type 1(11β HSD-1) inhibitors; melanocortin-3 receptor (Mc3r) agonists; andstearoyl-CoA desaturase-1 (SCD-1) compounds.

Non-limiting examples of nutrient absorption inhibitors useful in thepresent methods for treating or preventing a Condition include lipaseinhibitors (e.g., orlistat, lipstatin, tetrahydrolipstatin, teasaponinand diethylumbelliferyl phosphate); fatty acid transporter inhibitors;dicarboxylate transporter inhibitors; glucose transporter inhibitors;and phosphate transporter inhibitors.

Non-limiting examples of cholesterol biosynthesis inhibitors useful inthe present methods for treating or preventing a Condition includeHMG-CoA reductase inhibitors, squalene synthase inhibitors, squaleneepoxidase inhibitors, and mixtures thereof.

Non-limiting examples of cholesterol absorption inhibitors useful in thepresent methods for treating or preventing a Condition includeezetimibe. In one embodiment, the cholesterol absorption inhibitor isezetimibe.

HMG-CoA reductase inhibitors useful in the present methods for treatingor preventing a Condition include, but are not limited to, statins suchas lovastatin, pravastatin, fluvastatin, simvastatin, atorvastatin,cerivastatin, CI-981, resuvastatin, rivastatin, pitavastatin,rosuvastatin or L-659,699((E,E)-11-[3′R-(hydroxy-methyl)-4′-oxo-2′R-oxetanyl]-3,5,7R-trimethyl-2,4-undecadienoicacid).

Squalene synthesis inhibitors useful in the present methods for treatingor preventing a Condition include, but are not limited to, squalenesynthetase inhibitors; squalestatin 1; and squalene epoxidaseinhibitors, such as NB-598((E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[(3,3′-bithiophen-5-yl)methoxy}benzene-methanaminehydrochloride).

Bile acid sequestrants useful in the present methods for treating orpreventing a Condition include, but are not limited to, cholestyramine(a styrene-divinylbenzene copolymer containing quaternary ammoniumcationic groups capable of binding bile acids, such as QUESTRAN® orQUESTRAN LIGHT® cholestyramine which are available from Bristol-MyersSquibb), colestipol (a copolymer of diethylenetriamine and1-chloro-2,3-epoxypropane, such as COLESTID® tablets which are availablefrom Pharmacia), colesevelam hydrochloride (such as WelChol® Tablets(poly(allylamine hydrochloride) cross-linked with epichlorohydrin andalkylated with 1-bromodecane and (6-bromohexyl)-trimethylammoniumbromide) which are available from Sankyo), water soluble derivativessuch as 3,3-ioene, N-(cycloalkyl)alkylamines and poliglusam, insolublequaternized polystyrenes, saponins and mixtures thereof. Suitableinorganic cholesterol sequestrants include bismuth salicylate plusmontmorillonite clay, aluminum hydroxide and calcium carbonate antacids.Probucol derivatives useful in the present methods for treating orpreventing a Condition include, but are not limited to, AGI-1067 andothers disclosed in U.S. Pat. Nos. 6,121,319 and 6,147,250.

IBAT inhibitors useful in the present methods for treating or preventinga Condition include, but are not limited to, benzothiepines such astherapeutic compounds comprising a 2,3,4,5-tetrahydro-1-benzothiepine1,1-dioxide structure such as are disclosed in International PublicationNo. WO 00138727. Nicotinic acid receptor agonists useful in the presentmethods for treating or preventing a Condition include, but are notlimited to, those having a pyridine-3-carboxylate structure or apyrazine-2-carboxylate structure, including acid forms, salts, esters,zwitterions and tautomers, where available. Other examples of nicotinicacid receptor agonists useful in the present methods include nicotinicacid, niceritrol, nicofuranose and acipimox. An example of a suitablenicotinic acid product is NIASPAN® (niacin extended-release tablets)which are available from Kos Pharmaceuticals, Inc. (Cranbury, N.J.).Further nicotinic acid receptor agonists useful in the present methodsfor treating or preventing a Condition include, but are not limited to,the compounds disclosed in U.S. Patent Publication Nos. 2006/0264489 and2007/0066630, and U.S. patent application Ser. No. 11/771,538, each ofwhich is incorporated herein by reference.

ACAT inhibitors useful in the present methods for treating or preventinga Condition include, but are not limited to, avasimibe, HL-004,lecimibide and CL-277082(N-(2,4-difluorophenyl)-N-[[4-(2,2-dimethylpropyl)phenyl]-methyl]-N-heptylurea).See P. Chang et al., “Current, New and Future Treatments inDyslipidaemia and Atherosclerosis”, Drugs 2000 July; 60(1); 55-93, whichis incorporated by reference herein.

CETP inhibitors useful in the present methods for treating or preventinga Condition include, but are not limited to, those disclosed inInternational Publication No. WO 00/38721 and U.S. Pat. No. 6,147,090,each of which are incorporated herein by reference.

LDL-receptor activators useful in the present methods for treating orpreventing a Condition include, but are not limited to, include HOE-402,an imidazolidinyl-pyrimidine derivative that directly stimulates LDLreceptor activity. See M. Huettinger et al., “Hypolipidemic activity ofHOE-402 is Mediated by Stimulation of the LDL Receptor Pathway”,Arterioscler. Thromb. 1993; 13:1005-12.

Natural water-soluble fibers useful in the present methods for treatingor preventing a Condition include, but are not limited to, psyllium,guar, oat and pectin.

Fatty acid esters of plant stanols useful in the present methods fortreating or preventing a Condition include, but are not limited to, thesitostanol ester used in BENECOL® margarine.

Non-limiting examples of antidiabetic agents useful in the presentmethods for treating a Condition include insulin sensitizers,α-glucosidase inhibitors, DPP-IV inhibitors, insulin secretagogues,hepatic glucose output lowering compounds, antihypertensive agents,sodium glucose uptake transporter 2 (SGLT-2) inhibitors, insulin andinsulin-containing compositions, and anti-obesity agents as set forthabove.

In one embodiment, the antidiabetic agent is an insulin secretagogue. Inone embodiment, the insulin secretagogue is a sulfonylurea.

Non-limiting examples of sulfonylureas useful in the present methodsinclude glipizide, tolbutamide, glyburide, glimepiride, chlorpropamide,acetohexamide, gliamilide, gliclazide, gliquidone, glibenclamide andtolazamide.

In another embodiment, the insulin secretagogue is a meglitinide.

Non-limiting examples of meglitinides useful in the present methods fortreating a Condition include repaglinide, mitiglinide, and nateglinide.

In still another embodiment, the insulin secretagogue is GLP-1 or aGLP-1 mimetic.

Non-limiting examples of GLP-1 mimetics useful in the present methodsinclude Byetta-Exanatide, Liraglutinide, CJC-1131 (ConjuChem,Exanatide-LAR (Amylin), BIM-51077 (Ipsen/LaRoche), ZP-10 (ZealandPharmaceuticals), and compounds disclosed in International PublicationNo. WO 00/07617.

Other non-limiting examples of insulin secretagogues useful in thepresent methods include exendin, GIP and secretin.

In another embodiment, the antidiabetic agent is an insulin sensitizer.

Non-limiting examples of insulin sensitizers useful in the presentmethods include PPAR activators or agonists, such as troglitazone,rosiglitazone, pioglitazone and englitazone; biguanidines such asmetformin and phenformin; PTP-1B inhibitors; and glucokinase activators.

In another embodiment, the antidiabetic agent is a α-Glucosidaseinhibitor.

Non-limiting examples of α-Glucosidase inhibitors useful the presentmethods include miglitol, acarbose, and voglibose.

In another embodiment, the antidiabetic agent is an hepatic glucoseoutput lowering agent.

Non-limiting examples of hepatic glucose output lowering agents usefulin the present methods include Glucophage and Glucophage XR.

In yet another embodiment, the antidiabetic agent is insulin, includingall formualtions of insulin, such as long acting and short acting formsof insulin. Non-limiting examples of orally administrable insulin andinsulin containing compositions include AL-401 from Autoimmune, and thecompositions disclosed in U.S. Pat. Nos. 4,579,730; 4,849,405;4,963,526; 5,642,868; 5,763,396; 5,824,638; 5,843,866; 6,153,632;6,191,105; and International Publication No, WO 85/05029, each of whichis incorporated herein by reference.

In another embodiment, the antidiabetic agent is a DPP-IV inhibitor.

Non-limiting examples of DPP-IV inhibitors useful in the present methodsinclude sitagliptin, saxagliptin (Januvia™, Merck), denagliptin,vildagliptin (Galvus™, Novartis), alogliptin, alogliptin benzoate,ABT-279 and ABT-341 (Abbott), ALS-2-0426 (Alantos), ARI-2243 (Arisaph),BI-A and BI-B (Boehringer Ingelheim), SYR-322 (Takeda), MP-513(Mitsubishi), DP-893 (Pfizer), RO-0730699 (Roche) or a combination ofsitagliptin/metformin HCl (Janumet™, Merck).

In a further embodiment, the antidiabetic agent is a SGLT-2 inhibitor.

Non-limiting examples of SGLT-2 inhibitors useful in the present methodsinclude dapagliflozin and sergliflozin, AVE2268 (Sanofi-Aventis) andT-1095 (Tanabe Seiyaku).

Non-limiting examples of antihypertensive agents useful in the presentmethods for treating a Condition include β-blockers and calcium channelblockers (for example diltiazem, verapamil, nifedipine, amlopidine, andmybefradil), ACE inhibitors (for example captopril, lisinopril,enalapril, spirapril, ceranopril, zefenopril, fosinopril, cilazopril,and quinapril), AT-1 receptor antagonists (for example losartan,irbesartan, and valsartan), renin inhibitors and endothelin receptorantagonists (for example sitaxsentan).

In one embodiment, the antidiabetic agent is an agent that slows orblocks the breakdown of starches and certain sugars.

Non-limiting examples of antidiabetic agents that slow or block thebreakdown of starches and certain sugars and are suitable for use in thecompositions and methods of the present invention includealpha-glucosidase inhibitors and certain peptides for increasing insulinproduction. Alpha-glucosidase inhibitors help the body to lower bloodsugar by delaying the digestion of ingested carbohydrates, therebyresulting in a smaller rise in blood glucose concentration followingmeals. Non-limiting examples of suitable alpha-glucosidase inhibitorsinclude acarbose; miglitol; camiglibose; certain polyamines as disclosedin WO 01/47528 (incorporated herein by reference); voglibose.Non-limiting examples of suitable peptides for increasing insulinproduction including amlintide (CAS Reg. No. 122384-88-7 from Amylin;pramlintide, exendin, certain compounds having Glucagon-like peptide-1(GLP-1) agonistic activity as disclosed in International Publication No.WO 00/07617.

Other specific additional therapeutic agents useful in the presentmethods for treating or preventing a Condition include, but are notlimited to, rimonabant, 2-methyl-6-(phenylethynyl)-pyridine,3[(2-methyl-1,4-thiazol-4-yl)ethynyl]pyridine, Melanotan-II,dexfenfluramine, fluoxetine, paroxetine, fenfluramine, fluvoxamine,sertaline, imipramine, desipramine, talsupram, nomifensine, leptin,nalmefene, 3-methoxynaltrexone, naloxone, nalterxone, butabindide,axokine, sibutramine, topiramate, phytopharm compound 57, Cerulenin,theophylline, pentoxifylline, zaprinast, sildenafil, amrinone,milrinone, cilostamide, rolipram, cilomilast, phytanic acid,4-[(E)-2-(5,8,7,8-tetramethyl-2-naphthalenyl)-1-propenyllbenzoic acid,retinoic acid, oleoyl-estrone, orlistat, lipstatin, tetrahydrolipstatin,teasaponin and diethylumbelliferyl phosphate.

In one embodiment, the present combination therapies for treating orpreventing diabetes comprise administering a Substituted BiarylDerivative, an antidiabetic agent and/or an antiobesity agent.

In another embodiment, the present combination therapies for treating orpreventing diabetes comprise administering a Substituted BiarylDerivative and an antidiabetic agent.

In another embodiment, the present combination therapies for treating orpreventing diabetes comprise administering a Substituted BiarylDerivative and an anti-obesity agent.

In one embodiment, the present combination therapies for treating orpreventing obesity comprise administering a Substituted BiarylDerivative, an antidiabetic agent and/or an antiobesity agent.

In another embodiment, the present combination therapies for treating orpreventing obesity comprise administering a Substituted BiarylDerivative and an antidiabetic agent.

In another embodiment, the present combination therapies for treating orpreventing obesity comprise administering a Substituted BiarylDerivative and an anti-obesity agent.

In one embodiment, the present combination therapies for treating orpreventing metabolic syndrome comprise administering a SubstitutedBiaryl Derivative and one or more additional therapeutic agents selectedfrom: anti-obesity agents, antidiabetic agents, any agent useful fortreating metabolic syndrome, any agent useful for treating acardiovascular disease, cholesterol biosynthesis inhibitors, sterolabsorption inhibitors, bile acid sequestrants, probucol derivatives,IBAT inhibitors, nicotinic acid receptor (NAR) agonists, ACATinhibitors, cholesteryl ester transfer proten (CETP) inhibitors,low-denisity lipoprotein (LDL) activators, fish oil, water-solublefibers, plant sterols, plant stanols and fatty acid esters of plantstanols.

In one embodiment, the additional therapeutic agent is a cholesterolbiosynthesis inhibitor. In another embodiment, the cholesterolbiosynthesis inhibitor is a squalene synthetase inhibitor. In anotherembodiment, the cholesterol biosynthesis inhibitor is a squaleneepoxidase inhibitor. In still another embodiment, the cholesterolbiosynthesis inhibitor is an HMG-CoA reductase inhibitor. In anotherembodiment, the HMG-CoA reductase inhibitor is a statin. In yet anotherembodiment, the statin is lovastatin, pravastatin, simvastatin oratorvastatin.

In one embodiment, the additional therapeutic agent is a cholesterolabsorption inhibitor. In another embodiment, the cholesterol absorptioninhibitor is ezetimibe.

In one embodiment, the additional therapeutic agent comprises acholesterol absorption inhibitor and a cholesterol biosynthesisinhibitor. In another embodiment, the additional therapeutic agentcomprises a cholesterol absorption inhibitor and a statin. In anotherembodiment, the additional therapeutic agent comprises ezetimibe and astatin. In another embodiment, the additional therapeutic agentcomprises ezetimibe and simvastatin.

In one embodiment, the present combination therapies for treating orpreventing metabolic syndrome comprise administering a SubstitutedBiaryl Derivative, an antidiabetic agent and/or an antiobesity agent.

In another embodiment, the present combination therapies for treating orpreventing metabolic syndrome comprise administering a SubstitutedBiaryl Derivative and an antidiabetic agent.

In another embodiment, the present combination therapies for treating orpreventing metabolic syndrome comprise administering a SubstitutedBiaryl Derivative and an anti-obesity agent.

In one embodiment, the present combination therapies for treating orpreventing a cardiovascular disease comprise administering one or moreSubstituted Biaryl Derivatives, and an additional agent useful fortreating or preventing a cardiovascular disease.

When administering a combination therapy to a patient in need of suchadministration, the therapeutic agents in the combination, or apharmaceutical composition or compositions comprising the therapeuticagents, may be administered in any order such as, for example,sequentially, concurrently, together, simultaneously and the like. Theamounts of the various actives in such combination therapy may bedifferent amounts (different dosage amounts) or same amounts (samedosage amounts).

In one embodiment, the one or more Substituted Biaryl Derivatives areadministered during a time when the additional therapeutic agent(s)exert their prophylactic or therapeutic effect, or vice versa.

In another embodiment, the one or more Substituted Biaryl Derivativesand the additional therapeutic agent(s) are administered in dosescommonly employed when such agents are used as monotherapy for treatinga Condition.

In another embodiment, the one or more Substituted Biaryl Derivativesand the additional therapeutic agent(s) are administered in doses lowerthan the doses commonly employed when such agents are used asmonotherapy for treating a Condition.

In still another embodiment, the one or more Substituted BiarylDerivatives and the additional therapeutic agent(s) act synergisticallyand are administered in doses lower than the doses commonly employedwhen such agents are used as monotherapy for treating a Condition.

In one embodiment, the one or more Substituted Biaryl Derivatives andthe additional therapeutic agent(s) are present in the same composition.In one embodiment, this composition is suitable for oral administration.In another embodiment, this composition is suitable for intravenousadministration.

The one or more Substituted Biaryl Derivatives and the additionaltherapeutic agent(s) can act additively or synergistically. Asynergistic combination may allow the use of lower dosages of one ormore agents and/or less frequent administration of one or more agents ofa combination therapy. A lower dosage or less frequent administration ofone or more agents may lower toxicity of the therapy without reducingthe efficacy of the therapy.

In one embodiment, the administration of one or more Substituted BiarylDerivatives and the additional therapeutic agent(s) may inhibit theresistance of a Condition to these agents.

In one embodiment, when the patient is treated for diabetes or adiabetic complication, the additional therapeutic agent is anantidiabetic agent which is not a Substituted Biaryl Derivative. Inanother embodiment, the additional therapeutic agent is an agent usefulfor reducing any potential side effect of a Substituted BiarylDerivative. Such potential side effects include, but are not limited to,nausea, vomiting, headache, fever, lethargy, muscle aches, diarrhea,general pain, and pain at an injection site.

In one embodiment, the additional therapeutic agent is used at its knowntherapeutically effective dose. In another embodiment, the additionaltherapeutic agent is used at its normally prescribed dosage. In anotherembodiment, the additional therapeutic agent is used at less than itsnormally prescribed dosage or its known therapeutically effective dose.

The doses and dosage regimen of the other agents used in the combinationtherapies of the present invention for the treatment or prevention of aCondition can be determined by the attending clinician, taking intoconsideration the approved doses and dosage regimen in the packageinsert; the age, sex and general health of the patient; and the type andseverity of the viral infection or related disease or disorder. Whenadministered in combination, the Substituted Biaryl Derivative(s) andthe other agent(s) for treating diseases or conditions listed above canbe administered simultaneously or sequentially. This particularly usefulwhen the components of the combination are given on different dosingschedules, e.g., one component is administered once daily and anotherevery six hours, or when the preferred pharmaceutical compositions aredifferent, e.g. one is a tablet and one is a capsule. A kit comprisingthe separate dosage forms is therefore advantageous. Generally, a totaldaily dosage of the one or more Substituted Biaryl Derivatives and theadditional therapeutic agent(s)can when administered as combinationtherapy, range from about 0.1 to about 2000 mg per day, althoughvariations will necessarily occur depending on the target of thetherapy, the patient and the route of administration. In one embodiment,the dosage is from about 0.2 to about 100 mg/day, administered in asingle dose or in 2-4 divided doses. In another embodiment, the dosageis from about 1 to about 500 mg/day, administered in a single dose or in2-4 divided doses. In another embodiment, the dosage is from about 1 toabout 200 mg/day, administered in a single dose or in 2-4 divided doses.In still another embodiment, the dosage is from about 1 to about 100mg/day, administered in a single dose or in 2-4 divided doses. In yetanother embodiment, the dosage is from about 1 to about 50 mg/day,administered in a single dose or in 2-4 divided doses. In a furtherembodiment, the dosage is from about 1 to about 20 mg/day, administeredin a single dose or in 2-4 divided doses.

Compositions and Administration

In one embodiment, the invention provides compositions comprising aneffective amount of one or more Substituted Biaryl Derivatives or apharmaceutically acceptable salt, solvate, ester, prodrug orstereoisomer thereof, and a pharmaceutically acceptable carrier.

For preparing compositions comprising one or more Substituted BiarylDerivatives, inert, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,dispersible granules, capsules, cachets and suppositories. The powdersand tablets may be comprised of from about 5 to about 95 percent activeingredient. Suitable solid carriers are known in the art, e.g. magnesiumcarbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders,cachets and capsules can be used as solid dosage forms suitable for oraladministration. Examples of pharmaceutically acceptable carriers andmethods of manufacture for various compositions may be found in A.Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition,(1990), Mack Publishing Co., Easton, Pa.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection or addition of sweeteners and opacifiers fororal solutions, suspensions and emulsions. Liquid form preparations mayalso include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g., nitrogen.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

In one embodiment, a Substituted Biaryl Derivative is administeredorally.

In another embodiment, the pharmaceutical preparation is in a unitdosage form. In such form, the preparation is subdivided into suitablysized unit doses containing appropriate quantities of the activecomponent, e.g., an effective amount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation is fromabout 0.1 to about 2000 mg. Variations will necessarily occur dependingon the target of the therapy, the patient and the route ofadministration. In one embodiment, the unit dose dosage is from about0.2 to about 1000 mg. In another embodiment, the unit dose dosage isfrom about 1 to about 500 mg. In another embodiment, the unit dosedosage is from about 1 to about 100 mg/day. In still another embodiment,the unit dose dosage is from about 1 to about 50 mg. In yet anotherembodiment, the unit dose dosage is from about 1 to about 10 mg.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage regimen for a particular situation iswithin the skill of the art. For convenience, the total daily dosage maybe divided and administered in portions during the day as required.

The amount and frequency of administration of the compounds of theinvention and/or the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, the condition and size of the patient,as well as severity of the symptoms being treated. A typical recommendeddaily dosage regimen for oral administration can range from about 1mg/day to about 1000 mg/day, 1 mg/day to about 500 mg/day, 1 mg/day toabout 300 mg/day, 1 mg/day to about 75 mg/day, 1 mg/day to about 50mg/day, or 1 mg/day to about 20 mg/day, in one dose or in two to fourdivided doses.

When the invention comprises a combination of one or more SubstitutedBiaryl Derivatives and an additional therapeutic agent, the two activecomponents may be co-administered simultaneously or sequentially, or asingle composition comprising one or more Substituted Biaryl Derivativesand the additional therapeutic agent(s) in a pharmaceutically acceptablecarrier can be administered. The components of the combination can beadministered individually or together in any conventional dosage formsuch as capsule, tablet, powder, cachet, suspension, solution,suppository, nasal spray, etc. The dosage of the additional therapeuticagent can be determined from published material, and may range fromabout 1 to about 1000 mg per dose. In one embodiment, when used incombination, the dosage levels of the individual components are lowerthan the recommended individual dosages because of an advantageouseffect of the combination.

In one embodiment, the components of a combination therapy regimen areto be administered simultaneously, they can be administered in a singlecomposition with a pharmaceutically acceptable carrier.

In another embodiment, when the components of a combination therapyregimen are to be administered separately or sequentially, they can beadministered in separate compositions, each containing apharmaceutically acceptable carrier.

Kits

In one aspect, the present invention provides a kit comprising aneffective amount of one or more Compounds of Formula (I), or apharmaceutically acceptable salt or solvate of the compound and apharmaceutically acceptable carrier, vehicle or diluent.

In another aspect the present invention provides a kit comprising anamount of one or more Compounds of Formula (I), and an amount of one ormore additional therapeutic agents, wherein the combined amounts areeffective for enhancing the memory of a patient or effective fortreating or preventing a cognitive disorder in a patient.

When the components of a combination therapy regimen are to are to beadministered in more than one composition, they can be provided in a kitcomprising comprising: (a) one or more Compounds of Formula (I) togetherin a pharmaceutically acceptable carrier in a single container, or (b)one or more Compounds of Formula (I) in separate containers, each in apharmaceutically acceptable carrier, and (c) one or more additionaltherapeutic agents together in a pharmaceutically acceptable carrier ina single container or (d) one or more additional therapeutic agents inseparate containers, each in a pharmaceutically acceptable carrier; suchthat the active components of the combination therapy are present inamounts that render the combination therapeutically effective.

The present invention is not to be limited by the specific embodimentsdisclosed in the examples that are intended as illustrations of a fewaspects of the invention and any embodiments that are functionallyequivalent are within the scope of this invention. Indeed, variousmodifications of the invention in addition to those shown and describedherein will become apparent to those skilled in the art and are intendedto fall within the scope of the appended claims.

A number of references have been cited herein, the entire disclosures ofwhich are incorporated herein by reference.

What is claimed is:
 1. A compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein E is:

each occurrence of R⁶ is a ring carbon atom substituent and isindependently selected from halo, —CF₃, —OH, alkyl, C₃-C₇cycloalkyl and—O—alkyl; R¹⁵ is alkyl; and m is 0 or
 1. 2. The compound of claim 1, ora pharmaceutically acceptable salt thereof, wherein each occurrence ofR⁶ is halo.
 3. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein m is
 1. 4. The compound of claim 1, which is


5. A compound which is

or a pharmaceutically acceptable salt thereof.
 6. A compositioncomprising one or more compounds of claim 1 or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier.
 7. The composition of claim 6, further comprising one or moreadditional therapeutic agents, wherein the additional therapeuticagent(s) are selected from an antidiabetic agent and an antiobesityagent.
 8. A method for treating diabetes in a patient, the methodcomprising administering to the patient an effective amount of one ormore compounds of claim 1, or a pharmaceutically acceptable saltthereof.
 9. The method of claim 8, further comprising administering tothe patient one or more additional therapeutic agents, wherein theadditional therapeutic agent(s) are selected from an antidiabetic agentand an antiobesity agent.
 10. A compound having the structure:

or a pharmaceutically acceptable salt thereof.